We plan to study in some detail the thyroid gland physiology in health and disease as it pertains to the significance of some iodothyronines, only recently detected in human circulation, i.e., 3',5'-diiodothyronine (3',5'-T2), 3,3'-diiodothyronine (3,3'-T2) and 3,3'5'-triiodothyronine (reverse T3, rT3); the results will be examined in the light of similar information on other, relatively better known iodothyronines, i.e., 3,5,3'-triiodothyronine (T3) and Thyroxine (T4). We shall use the newly developed antisera for radioimmunoassay of 3',5'-T2, 3,3'-T2, rT3 and the well-established radioimmunoassays of T3 and T4 to study: 1) the relative serum concentrations of 3', 5'-T2, 3,3'-T2, rT3, T3 and T4 in health and disease including several situations where serum T3 is low and rT3 high, e.g., calorie-deprivation states, systemic illnesses such as hepatic cirrhosis, fetus and the newborn; (2) daily production rates of 3,3'-T2, 3',5'-T2, rT3, T3 and T4 in thyroid disease, complete fasting and/or hepatic cirrhosis; (3) the characteristics of alterations of amniotic fluid concentrations of iodothyronines in complicated pregnancy; (4) the usefulness in treatment of hyperthyroidism of agents, e.g., oragrafin, that act predominantly by inhibiting conversion of T4 to T3; (5) the nature of and the intracellular location of the processes of monodeiodination of T4 to T3 and rT3; rT3 to 3,3'-T2 and 3',5'-T2; T3 to 3,3'-T2 and 3,5-T2; (6) purification of the monodeiodinating activities referred to in #5; (7) the mechanism of action of drugs, e.g. oragrafin, that inhibit conversion of T4 to T3 and of rT3 to 3,3'-T2; (8) the mechanism of reduced conversion of T4 to T3 in sheep fetus, the starved rat and the uremic rat. We also plan to study the presence in human circulation of the acetic acid and propionic acid analogues of T3 in health and disease as well as the conversion of T3 to these analogs.